Institute of Biotechnology & Research Programs Unit, Genome-Scale-Biology, Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Oncogene. 2013 Feb 28;32(9):1091-8. doi: 10.1038/onc.2012.118. Epub 2012 Apr 2.
Primary effusion lymphomas (PELs) are aggressive Kaposi's sarcoma herpesvirus (KSHV)-induced malignancies with median survival time <6 months post-diagnosis. Mutations in the TP53 gene seldom occur in PELs, suggesting that genetic alterations in the TP53 are not selected during PEL progression. We have reported that p53 reactivation by an inhibitor of the p53-MDM2 interaction, Nutlin-3, induces selective and massive apoptosis in PEL cells leading to efficient anti-tumor activity in a subcutaneous xenograft model for PEL. Here, we show compelling anti-tumor activity of Nutlin-3 in the majority of intraperitoneal PEL xenografts in vivo. Interestingly, our results demonstrate that spontaneous induction of viral lytic replication in tumors could drastically attenuate the p53-dependent apoptotic response to Nutlin-3. Moreover, viral reactivation compromised p53-dependent apoptosis in PEL cells treated with genotoxic anti-cancer agents doxorubicin and etoposide. We have recently demonstrated that the Ser/Thr kinases Pim 1 and 3 are required to trigger induction of the lytic replication cascade of KSHV. We have now assessed the ability of a novel Pim kinase inhibitor to restore the Nutlin-3-induced cytotoxicity in lytic PEL cells. PEL cells induced to lytic replication by phorbol esters showed 50% inhibition of active viral replication following treatment with the Pim kinase inhibitor. Importantly, co-treatment of these cells with the kinase inhibitor and Nutlin-3 resulted in a robust restoration of the Nutlin-3-induced cell death. These results highlight the potential impact of activation of viral lytic replication on disease progression and response to treatment in KSHV-induced lymphomas.
原发性渗出性淋巴瘤（PELs）是一种侵袭性的卡波西肉瘤疱疹病毒（KSHV）诱导的恶性肿瘤，诊断后中位生存时间<6 个月。TP53 基因突变在 PEL 中很少发生，这表明在 PEL 进展过程中，TP53 的遗传改变并未被选择。我们曾报道，p53-MDM2 相互作用抑制剂 Nutlin-3 可使 p53 重新激活，导致 PEL 细胞发生选择性和大量凋亡，在 PEL 的皮下异种移植模型中具有高效的抗肿瘤活性。在此，我们在体内大多数腹腔 PEL 异种移植模型中证实了 Nutlin-3 的显著抗肿瘤活性。有趣的是，我们的结果表明，肿瘤中自发性诱导病毒裂解复制可大大减弱 Nutlin-3 对 p53 依赖性凋亡的反应。此外，病毒重新激活使经多柔比星和依托泊苷等细胞毒性抗癌药物处理的 PEL 细胞中的 p53 依赖性凋亡受损。我们最近证明，丝氨酸/苏氨酸激酶 Pim1 和 3 是触发 KSHV 裂解复制级联诱导所必需的。我们现在评估了一种新型 Pim 激酶抑制剂恢复裂解性 PEL 细胞中 Nutlin-3 诱导细胞毒性的能力。用佛波酯诱导裂解复制的 PEL 细胞经 Pim 激酶抑制剂处理后，活跃的病毒复制有 50%受到抑制。重要的是，用激酶抑制剂和 Nutlin-3 共同处理这些细胞，可显著恢复 Nutlin-3 诱导的细胞死亡。这些结果突出了病毒裂解复制的激活对 KSHV 诱导的淋巴瘤疾病进展和治疗反应的潜在影响。
